Artificial dialysis is practiced for patients with end-stage renal failure through chronic renal failure as a result of progression of chronic kidney disease (CKD). CKD results in abnormal bone or mineral metabolism and causes a cardiovascular disease at a high incidence. This cardiovascular disease is the main cause of death in CKD patients. In CKD patients, a reduced bone mass as well as ectopic calcification including vascular calcification is observed with high frequency. The ectopic calcification is reported to be a process which is controlled by both progression and suppression. The main mechanisms of the ectopic calcification are considered to contain an attenuated process of suppression of calcification, induction of bone or cartilage formation, cell death, abnormal calcium and phosphorus homeostasis, the presence of calcium phosphate, substrate decomposition, etc. (Non Patent Literature 1).
Among the ectopic calcification cases, a phenomenon in which insoluble calcium phosphate, etc., is deposited in arterial vessels etc. is called vascular calcification. The vascular calcification is classified as follows: medial calcification, called Monckeberg's type, found in aged people, diabetic patients and CKD patients, and arteriosclerotic calcification of artherosclerotic plaques in the intima (atheroma intimal calcification) (Non Patent Literature 2). Examples of the former include ectopic calcification disorders (including induction by active vitamin D preparations) significantly found, particularly, in long-term artificial dialysis patients. On the other hand, the course of progression of the latter is considered to involve the accumulation of excessive lipids and macrophages to arteriosclerotic plaques as in the conventional mechanism of arteriosclerosis (Non Patent Literature 3).
The process of formation of Monckeberg's medial calcification presumably has a mechanism of differentiation of vascular smooth muscle cells to osteoblasts. Risk factors for vascular calcification include age, the duration of dialysis, diabetes mellitus, hypertension, phosphorus concentrations in blood, calcium-phosphate products, and medication with calcium-comprising phosphate binders (which are used for the purpose of treating secondary hyperparathyroidism in CKD), etc. (Non Patent Literature 4).
For CKD, it has been suggested that vascular calcification as a complication increases morbidities and mortalities of cardiovascular diseases (Non Patent Literature 5). Particularly, the treatment of vascular calcification is essential for decreasing the number of deaths of CKD patients.
However, treatment methods effective for ectopic calcification diseases and vascular calcification disorders have not yet been adequately established under these circumstances. For example, the administration of phosphate binders (calcium-comprising phosphate binders, polymeric phosphate binders, lanthanum carbonate, etc.) or calcium analogs has been attempted, but does not exert adequate drug efficacy. There has been a growing need of methods for effectively inhibiting and preventing vascular calcification with increase in CKD patients or patients with diseases involving arteriosclerosis. The development of novel effective medicines has been desired.
Etidronate, which is one of the bisphosphonate compounds, is effective as a therapeutic agent for osteoporosis by promoting increase in bone mass through its bone resorption inhibitory effect, while this compound shows the effect of inhibiting bone formation (bone calcification) at a higher dose than that produces the bone resorption inhibitory effect and is used as a therapeutic agent for ectopic ossification. In a test to which dialysis patients are subjected, etidronate has been reported to significantly inhibit calcification in the aorta (Non Patent Literature 6). Etidronate has further been reported to significantly decrease the carotid artery intima-media thicknesses of type 2 diabetic patients (Non Patent Literature 7).
According to the reports as to bisphosphonate compounds other than etidronate, nitrogen-comprising bisphosphonate drugs exhibited no calcification inhibitory effect in humans (Non Patent Literatures 8 and 9). There is also a report on the administration of bisphosphonate drugs to humans with the aim of ameliorating hypercalcemia, for example (Patent Literature 1). Furthermore, rat calcification models (Patent Literature 2), atherosclerosis models (Patent Literature 3) and rat hypercalcemia models (Patent Literature 4) have been reported as study cases of the effects of bisphosphonate compounds in animals. Although such reports, albeit a few in number, have been made, there is almost no finding about a bisphosphonate compound specific for ectopic calcification.